Dataset Information

Synthesis and evaluation of 13C-labeled 5-5-dimethyl-1-pyrroline-N-oxide aimed at in vivo detection of reactive oxygen species using hyperpolarized 13C-MRI.

ABSTRACT: Effective means to identify the role of reactive oxygen species (ROS) mediating several diseases including cancer, ischemic heart disease, stroke, Alzheimer's and other inflammatory conditions in in vivo models would be useful. The cyclic nitrone 5,5-Dimethyl-1-pyrroline-N-oxide (DMPO) is a spin trap frequently used to detect free radicals in vitro using Electron Paramagnetic Resonance (EPR) spectroscopy. In this study, we synthesized 13C-labeled DMPO for hyperpolarization by dynamic nuclear polarization, in which 13C NMR signal increases more than 10,000-fold. This allows in vivo 13C MRI to investigate the feasibility of in vivo ROS detection by the 13C-MRI. DMPO was 13C-labeled at C5 position, and deuterated to prolong the T1 relaxation time. The overall yield achieved for 5-13C-DMPO-d9 was 15%. Hyperpolarized 5-13C-DMPO-d9 provided a single peak at 76?ppm in the 13C-spectrum, and the T1 was 60?s in phosphate buffer making it optimal for in vivo 13C MRI. The buffered solution of hyperpolarized 5-13C-DMPO-d9 was injected into a mouse placed in a 3?T scanner, and 13C-spectra were acquired every 1?s. In vivo studies showed the signal of 5-13C-DMPO-d9 was detected in the mouse, and the T1 decay of 13C signal of hyperpolarized 5-13C-DMPO-d9 was 29?s. 13C-chemical shift imaging revealed that 5-13C-DMPO-d9 was distributed throughout the body in a minute after the intravenous injection. A strong signal of 5-13C-DMPO-d9 was detected in heart/lung and kidney, whereas the signal in liver was small compared to other organs. The results indicate hyperpolarized 5-13C-DMPO-d9 provided sufficient 13C signal to be detected in the mouse in several organs, and can be used to detect ROS in vivo.

SUBMITTER: Saito K

PROVIDER: S-EPMC6983923 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

Synthesis and evaluation of 13C-labeled 5-5-dimethyl-1-pyrroline-N-oxide aimed at in vivo detection of reactive oxygen species using hyperpolarized 13C-MRI.

Saito Keita K Sail Deepak D Yamamoto Kazutoshi K Matsumoto Shingo S Blackman Burchelle B Kishimoto Shun S Brender Jeffrey R JR Swenson Rolf E RE Mitchell James B JB Krishna Murali C MC

Free radical biology & medicine 20181122

Effective means to identify the role of reactive oxygen species (ROS) mediating several diseases including cancer, ischemic heart disease, stroke, Alzheimer's and other inflammatory conditions in in vivo models would be useful. The cyclic nitrone 5,5-Dimethyl-1-pyrroline-N-oxide (DMPO) is a spin trap frequently used to detect free radicals in vitro using Electron Paramagnetic Resonance (EPR) spectroscopy. In this study, we synthesized 13C-labeled DMPO for hyperpolarization by dynamic ...[more]

PMID: 30471347

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Project description:MRI using hyperpolarized (HP) carbon-13 pyruvate is being investigated in clinical trials to provide non-invasive measurements of metabolism for cancer and cardiac imaging. In this project, we applied HP [1-13 C]pyruvate dynamic MRI in prostate cancer to measure the conversion from pyruvate to lactate, which is expected to increase in aggressive cancers. The goal of this work was to develop and test analysis methods for improved quantification of this metabolic conversion. In this work, we compared specialized kinetic modeling methods to estimate the pyruvate-to-lactate conversion rate, kPL , as well as the lactate-to-pyruvate area-under-curve (AUC) ratio. The kinetic modeling included an "inputless" method requiring no assumptions regarding the input function, as well as a method incorporating bolus characteristics in the fitting. These were first evaluated with simulated data designed to match human prostate data, where we examined the expected sensitivity of metabolism quantification to variations in kPL , signal-to-noise ratio (SNR), bolus characteristics, relaxation rates, and B1 variability. They were then applied to 17 prostate cancer patient datasets. The simulations indicated that the inputless method with fixed relaxation rates provided high expected accuracy with no sensitivity to bolus characteristics. The AUC ratio showed an undesired strong sensitivity to bolus variations. Fitting the input function as well did not improve accuracy over the inputless method. In vivo results showed qualitatively accurate kPL maps with inputless fitting. The AUC ratio was sensitive to bolus delivery variations. Fitting with the input function showed high variability in parameter maps. Overall, we found the inputless kPL fitting method to be a simple, robust approach for quantification of metabolic conversion following HP [1-13 C]pyruvate injection in human prostate cancer studies. This study also provided initial ranges of HP [1-13 C]pyruvate parameters (SNR, kPL , bolus characteristics) in the human prostate.

Dataset Information

Synthesis and evaluation of 13C-labeled 5-5-dimethyl-1-pyrroline-N-oxide aimed at in vivo detection of reactive oxygen species using hyperpolarized 13C-MRI.

Publications

Synthesis and evaluation of <sup>13</sup>C-labeled 5-5-dimethyl-1-pyrroline-N-oxide aimed at in vivo detection of reactive oxygen species using hyperpolarized <sup>13</sup>C-MRI.

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